The present invention relates to nonanoic acid derivatives, their synthesis, and their use as xcex1v integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors xcex1vxcex23, xcex1vxcex25, and xcex1v integrin receptors associated with other xcex2-subunits, and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, and metastatic tumor growth.
It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs. Integrin receptors are heterodimeric transmembrane receptors through which cells attach and communicate with extracellular matrices and other cells. (See S. B. Rodan and G. A. Rodan, xe2x80x9cIntegrin Function In Osteoclasts,xe2x80x9d Journal of Endocrinology, 154: S47-S56 (1997), which is incorporated by reference herein in its entirety).
In one aspect of the present invention, the compounds herein are useful for inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multinucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone.
Integrins are involved in osteoclast attachment, activation and migration. The most abundant integrin on osteoclasts, e.g., on rat, chicken, mouse and human osteoclasts, is an integrin receptor known as xcex1vxcex23, which is thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to xcex1vxcex23 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that xcex1vxcex23 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget""s disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Additionally, xcex1vxcex23 ligands have been found to be useful in treating and/or inhibiting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (i.e. formation of new blood vessels), and inhibiting viral disease. Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models (See Harrison""s Principles of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, xcex1vxcex23 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, 79:1157-1164 (1994), which is incorporated by reference herein in its entirety).
Evidence has also been presented suggesting that angiogenesis is a central factor in the initiation and persistence of arthritic disease, and that the vascular integrin xcex1vxcex23 may be a preferred target in inflammatory arthritis. Therefore, xcex1vxcex23 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthritic disease, such as rheumatoid arthritis (see C. M. Storgard, et al., xe2x80x9cDecreased angiogenesis and arthritic disease in rabbits treated with an xcex1vxcex23 antagonist,xe2x80x9d J. Clin. Invest., 103: 47-54 (1999), which is incorporated by reference herein in its entirety).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, xcex1vxcex25. A monoclonal antibody for xcex1vxcex25 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M. C. Friedlander, et.al., Science 270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize xcex1vxcex25 are useful for treating and preventing macular degeneration, diabetic retinopathy, viral disease, cancer, and metastatic tumor growth.
Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of xcex1v integrin receptors associated with other xcex2 subunits, suh as xcex1vxcex26 and xcex1vxcex28. (see, for example, Melpo Christofidou-Solomidou, et al., xe2x80x9cExpression and Function of Endothelial Cell xcex1v Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras,xe2x80x9d American Journal of Pathology, 151: 975-83 (1997) and Xiao-Zhu Huang, et al., xe2x80x9cInactivation of the Integrin xcex26 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin, Journal of Cell Biology,xe2x80x9d 133: 921-28 (1996), which are incorporated by reference herein in their entirety).
In addition, certain compounds of this invention antagonize both the xcex1vxcex23 and xcex1vxcex25 receptors. These compounds, referred to as xe2x80x9cdual xcex1vxcex23/xcex1vxcex25 antagonists,xe2x80x9d are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, cancer, and metastatic tumor growth.
Peptidyl as well as peptidomimetic antagonists of the xcex1vxcex23 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W. J. Hoekstra and B. L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO 99/15506; WO 99/15507; WO 99/31061; WO 00/06169; EP 853084; EP 854140; EP 854145; U.S. Pat. No. 5,780,426; and U.S. Pat. No. 6,048,861. Evidence of the ability of xcex1vxcex23 integrin receptor antagonists to prevent bone resorption in vitro and in vivo has been presented (see V. W. Engleman et al., xe2x80x9cA Peptidomimetic Antagonist of the xcex1vxcex23 Integrin Inhibits Bone Resorption in Vitro and Prevents Osteoporosis in Vivo,xe2x80x9d J. Clin. Invest. 99: 2284-2292 (1997); S. B. Rodan et al., xe2x80x9cA High Affinity Non-Peptide xcex1vxcex23 Ligand Inhibits Osteoclast Activity In Vitro and In Vivo,xe2x80x9d J. Bone Miner. Res. 11: S289 (1996); J. F. Gourvest et al., xe2x80x9cPrevention of OVX-Induced Bone Loss With a Non-peptidic Ligand of the xcex1vxcex23 Vitronectin Receptor,xe2x80x9d Bone 23: S612 (1998); M. W. Lark et al., xe2x80x9cAn Orally Active Vitronectin Receptor xcex1vxcex23 Antagonist Prevents Bone Resorption In Vitro and In Vivo in the Ovariectomized Rat,xe2x80x9d Bone 23: S219 (1998)).
The xcex1vxcex23 integrin receptor recognizes the Arg-Gly-Asp (RGD) tripeptide sequence in its cognate matrix and cell surface glycoproteins (see J. Samanen, et al., xe2x80x9cVascular Indications for Integrin xcex1v Antagonists,xe2x80x9d Curr. Pharmaceut. Design 3: 545-584 (1997)). A benzazepine nucleus has been employed among others by Genentech and SmithKline Beecham as a conformationally constrained Gly-Asp mimetic to elaborate nonpeptide xcex1vxcex23 integrin receptor antagonists substituted at the N-terminus with heterocyclic arginine mimetics (see R. M. Keenan et al., xe2x80x9cDiscovery of Potent Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonists,xe2x80x9d J. Med. Chem. 40: 2289-2292 (1997); R. M. Keenan et al., xe2x80x9cBenzimidazole Derivatives As Arginine Mimetics in 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonists,xe2x80x9d Bioorg. Med. Chem. Lett. 8: 3165-3170 (1998); and R. M. Keenan et al., xe2x80x9cDiscovery of an Imidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonist With Efficacy in a Restenosis Model,xe2x80x9d Bioorg. Med. Chem. Lett. 8: 3171-3176 (1998). Patents assigned to SmithKline Beecham that disclose such benzazepine, as well as related benzodiazepine and benzocycloheptene, xcex1vxcex23 integrin receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, and WO 99/15178, and to Genentech include WO 97/34865. The dibenzocycloheptene, as well as dibenzoxazepine, nucleus has also been employed as a Gly-Asp mimetic to afford xcex1vxcex23 antagonists (see WO 97/01540, WO 98/30542, WO 99/11626, and WO 99/15508 all assigned to SmithKline Beecham).
Other integrin receptor antagonists featuring backbone conformational ring constraints have been described in WO 98/08840; WO 99/30709; WO 99/30713; WO 99/31099; WO 00/09503; U.S. Pat. No. 5,919,792; U.S. Pat. No. 5,925,655; U.S. Pat. No. 5,981,546; and U.S. Pat. No. 6,017,926.
However, there still remains a need for small-molecule, non-peptidic selective xcex1v integrin receptor antagonists that display improved potency, pharmacodynamic, and pharmacokinetic properties, such as oral bioavailability and duration of action, over already described compounds. Such compounds would prove to be useful for the treatment, prevention, or suppression of various pathologies enumerated above that are mediated by xcex1v integrin receptor binding and cell adhesion and activation.
In U.S. Pat. No. 6,048,861 (Apr. 11, 2000), we disclosed, inter alia, a series of 3-substituted nonanoic acid derivatives which are potent xcex1vxcex23 integrin receptor antagonists. In the present invention, we describe analogous alkanoic acid derivatives which are substituted at the C-5 or C-7 position of the aliphatic chain with an oxygen functionality, such as hydroxy and keto, and at C-3 with an optionally substituted aryl group. When compared to the parent compounds, the chain-oxygenated compounds of the instant invention are less hydrophobic, show decreased binding to plasma proteins, and exhibit superior in vivo pharmacokinetic and/or pharmacodynamic properties.
It is therefore an object of the present invention to provide novel nonanoic acid derivatives oxygenated at the C-5 or C-7 position of the aliphatic chain which are useful as xcex1v integrin receptor antagonists.
It is another object of the present invention to provide novel nonanoic acid derivatives oxygenated at the C-5 or C-7 position of the aliphatic chain which are useful as xcex1vxcex23 receptor antagonists.
It is another object of the present invention to provide novel nonanoic acid derivatives oxygenated at the C-5 or C-7 position of the aliphatic chain which are useful as xcex1vxcex25 receptor antagonists.
It is another object of the present invention to provide novel nonanoic acid derivatives oxygenated at the C-5 or C-7 position of the aliphatic chain which are useful as dual xcex1vxcex23/xcex1vxcex25 receptor antagonists.
It is another object of the present invention to provide pharmaceutical compositions comprising integrin receptor antagonists.
It is another object of the present invention to provide methods for making the pharmaceutical compositions of the present invention.
It is another object of the present invention to provide methods for eliciting an integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth.
It is another object of the present invention to provide compounds and pharmaceutical compositions useful for treating osteoporosis.
It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth.
It is another object of the present invention to provide methods for treating osteoporosis.
These and other objects will become readily apparent from the detailed description which follows.
The present invention relates to novel compounds represented by structural formula (I): 
wherein:
X is selected from the group consisting of 
Y is CH2; O; or NR1;
each R1 is independently hydrogen or C1-3 alkyl and each non-aromatic ring carbon atom is unsubstituted or independently substituted with one or two R2 substituents and each aromatic ring carbon atom is unsubstituted or independently substituted with one R2 substituent selected from the group consisting of
halogen, C1-8 alkyl, C3-8 cycloalkyl,
C3-8 cycloheteroalkyl, C3-8 cycloalkyl-C1-6 alkyl,
C3-8 cycloheteroalkyl-C1-6 alkyl, aryl, aryl-C1-6 alkyl, amino,
amino-C1-6 alkyl, C1-3 acylamino, C1-3 acylamino-C1-6 alkyl,
(C1-6 alkyl)1-2 amino, C3-6 cycloalkyl-C0-2 amino,
(C1-6 alkyl)1-2 amino-C1-6 alkyl, C1-6 alkoxy, C1-4 alkoxy-C1-6 alkyl,
hydroxycarbonyl, hydroxycarbonyl-C1-6 alkyl, C1-3 alkoxycarbonyl,
C1-3 alkoxycarbonyl-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl,
nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy,
C1-8 alkyl-S(O)0-2, (C1-8 alkyl)0-2 aminocarbonyl,
C1-8 alkyloxycarbonylamino, (C1-8 alkyl)1-2 aminocarbonyloxy,
(aryl C1-3 alkyl)1-2 amino, (aryl)1-2 amino,
aryl-C1-3 alkylsulfonylamino, and C1-8 alkylsulfonylamino;
or two R2 substituents, when on the same non-aromatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group, or two R2 substituents, together with the carbon atoms to which they are attached, join to form a 4- to 6-membered saturated or unsaturated carbocyclic ring;
R3 and R5 are each independently hydrogen, hydroxy, or C1-6 alkoxy;
R4 and R6 are each independently hydrogen or C1-3 alkyl; or
R3 and R4 taken together or R5 and R6 taken together are carbonyl oxygen, with the proviso that both R3 and R5 are not simultaneously hydrogen;
R7 is aryl wherein the aryl group is selected from the group consisting of
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) pyrrolyl,
(7) oxazolyl,
(8) thiazolyl,
(9) imidazolyl,
(10) pyrazolyl,
(11) isoxazolyl,
(12) isothiazolyl,
(13) pyrimidinyl,
(14) pyrazinyl,
(15) pyridazinyl,
(16) tetrazolyl,
(17) quinolyl,
(18) isoquinolyl,
(19) benzimidazolyl,
(20) benzofuryl,
(21) benzothienyl,
(22) indolyl,
(23) benzthiazolyl,
(24) benzoxazolyl,
(25) dihydrobenzofuryl,
(26) benzo(1,3)dioxolanyl,
(27) benzo(1,4)dioxanyl,
(28) quinazolyl,
(29) quinoxalyl, and
(30) 3,4-dihydro-2H-1,4-dioxa-5-aza-naphthalenyl;
wherein the aryl group as defined above in items (1) to (30) is unsubstituted or substituted with one to three substituents independently selected from hydroxy, hydroxy-C1-6 alkyl, halogen, C1-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, amino, amino C1-6 alkyl, C1-3 acylamino, C1-3 acylamino-C1-6 alkyl, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylarnino-C1-6 alkyl, di(C1-6) alkylamino-C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkoxy-C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl-C1-6 alkyl, C1-5 alkylcarbonyloxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, and nitro; or two adjacent substituents together with the carbon atoms to which they are attached join to form a five- or six-membered saturated or unsaturated ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, whose ring carbon atoms may be substituted with oxo or C1-3 alkyl; with the proviso that if X is 5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl, R2 is hydrogen, and aryl is 6-substituted-pyridin-3-yl, then the 6-substituent on the pyridin-3-yl ring is other than methoxy; and
R8 is hydrogen or C1-3 alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are useful as xcex1v integrin receptor antagonists.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
The present invention also relates to methods for making the pharmaceutical compositions of the present invention.
The present invention also relates to methods for eliciting an xcex1v integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.